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Division of Clinical
Neurology, Department of Medicine, University Hospital, Queen's
Medical Centre, Nottingham, UK
Correspondence to: Professor LD Blumhardt, Division of Clinical Neurology, Department of Medicine, University Hospital, Queen's Medical Centre, Nottingham NG7 2UH, UK
Received 20 July 1999 and in revised form 12 November 1999;
Accepted 25 November
1999
OBJECTIVES
Recent
phase III clinical trials of immunomodulatory therapies in
relapsing-remitting multiple sclerosis have shown significant benefits
of active treatment on relapse related end points, but effects on
disability outcomes have been inconsistent. These apparent discrepancies could be due to differences in the clinical end points
employed, the behaviour of placebo cohorts, or both.
METHODSDisability
data from the placebo cohorts of two large phase III studies, the
United States glatiramer acetate trial (Copolymer 1 Multiple Sclerosis
Study Group) and the multinational interferon 
-1a trial (PRISMS
Study Group) were combined and masked (n=313). Two groups of disability
outcome measures were assessed. Firstly, measures of disability change
(2 year EDSS difference and area under the EDSS/time curve, AUC) were
calculated. Secondly, conventional disease progression end points
("confirmed progression" and "worsening to EDSS 6.0") were
evaluated by using Kaplan-Meier analysis and compared with a
categorical classification based on EDSS trends.
RESULTSThe average
increase in disability for the entire cohort as assessed by mean 2 year
EDSS change (<0.5 EDSS point) or mean AUC (+0.57 EDSS-years) was
small. For the "confirmed progression" end points, increasing the
stringency of the definition lowered their incidence (from 32% with
1.0 point at 3 months, to 9% with 2.0 points at 6 months), but did not
improve the positive predictive accuracy for "sustained
progression" maintained to the end of the study. The error rate for
this outcome was about 50%. Worsening to EDSS 6.0 was a more reliable
end point, but had even lower sensitivity (incidence <10%). EDSS
trend analysis showed markedly heterogeneous disease courses, which
were then categorised into "stable" (26%),
"relapsing-remitting" (59%), and "progressive" (15%) courses.
Patients with the last course had deteriorated considerably by the end
of 2 years (mean worsening of 2.0 EDSS points).
CONCLUSIONIn
relapsing-remitting multiple sclerosis treatment trials, the
conventional measure of mean EDSS change has low sensitivity, whereas
the widely applied confirmed progression end points have high error
rates regardless of their definition stringency. Alternative methods
with better data utilisation include AUC summary measures and
categorical disease trend analysis. The heterogeneity of disability outcomes in short trials, combined with unreliable clinical end points,
diminishes the credibility of therapeutic claims aimed at reducing
irreversible neurological deficits. The behaviour of patients treated
with placebo should be carefully analysed before conclusions are drawn
on the efficacy of putative treatments.
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